Daily administration of m-chlorophenylpiperazine (m-CPP), a serotonergic agent, to healthy volunteers led to a rapid development of tolerance over the course of three days indicated by significant attenuations of the effects of m-CPP on anxiety, temperature, pupil size, diastolic blood pressure and plasma hormone concentrations (cortisol, ACTH, prolactin). In clinical studies of selective serotonin antagonists, ondansetron had modest effects on the duration of the neuroendocrine and behavioral responses to m-CPP and to d-amphetamine, while metergoline reversed some of the therapeutic effects of fluoxetine in patients with obsessive- compulsive disorder. In collaborative studies, exaggerated neuroendocrine responses to m-CPP were found in seasonal affective disorder patients compared to controls. In a study using a standardized test meal, m-CPP-induced food intake reductions were of equal magnitude in bulimic patients and controls. In a study using temperature probes at multiple sites, m-CPP-induced temperature changes were found to be biphasic, and to be strongly correlated with the temperature minimum on the night prior to the study. No abnormalities were found in the protein coding regions of the cell membrane serotonin transporter or the vesicular monoamine transporter in patients with unipolar depression or bipolar disorder.